A natural killer cell (hereinafter abbreviated as “NK cell”) is activated by interferon and interleukin-2 (hereinafter abbreviated as “IL2”), and the activated cell destroys tumor cells and such. While the biological defense mechanism dependent on T cells and B cells functions as a result of immune response, the NK cell-dependent defense mechanism works via the activation by cytokines. Namely, the complicated process of immune response is not required for the defensive function of NK cells. Therefore, NK cells have been believed to play an important role at the forefront of the biological defense mechanisms.
Thus, the biological defense mechanisms may be controlled by modifying the activation and proliferation of NK cells. However, many obscurities regarding the function of NK cells remain to be clarified.
On the other hand, NK cells are lymphocytes and form lymphomas upon tumorigenic transformation. For example, primary nasal angiocentric NK lymphoma is a lymphoma found in Asian countries. Primary nasal angiocentric NK lymphomas are generally resistant to various anti-cancer agents and often have a bad prognosis. Thus, elucidation of the mechanism of NK cell tumorigenesis is an important object for developing therapeutic methods against this disease.
Infection with Epstein-Barr virus (hereinafter abbreviated as “EBV”) has been suggested to be involved in the development lymphoma. For example, using a cell line established from Burkitt's lymphoma (hereinafter abbreviated as “BL”), the influence of the EBV genome on B cell lymphoma has been reported (Journal of Virology 6069-6073, 1994, “Isolation of Epstein-Barr Virus (EBV)-negative cell clones from the EBV-positive Burkitt's lymphoma (BL) line Akata: malignant phenotypes of BL cell are dependent on EBV.”). According to this report, malignant phenotypes of BL were induced in EBV-negative Akata cells by infection of EBV into the cells. However, there is no report describing the involvement of EBV with NK cells. Thus, elucidation of the mechanism underlying the tumorigenesis of NK cells is desired in the art. In particular, once an EBV-negative NK cell line is established, such a cell line can serve as an important research tool for studying the effect of EBV on NK cells.
NK cell lines are useful for performing studies on NK cells, e.g., studies on the regulation of activation and proliferation of NK cells, the mechanism underlying NK cell tumorigenesis, etc. When such a cell line is made available, a common cell can be easily shared by many researchers. Most importantly, the use of a cell line obviates the need to use fresh blood as an experimental tool, which would facilitate the performance of such experiments.
The present inventors have already established a cell line NK-YS derived from NK lymphoma (Blood 192: 1374-1383, 1998). The NK cell line NK-YS is an EBV-positive cell line. To assess the involvement of EBV, it is expected to establish an EBV-negative cell line.
As described above, the establishment of an EBV-negative cell line from an Akata cell that is a B-cell lymphoma-derived cell line has been reported. The elimination of EBV in B cells occurs due to long-term passage of EBV-positive lymphoma-derived cells. This enabled the establishment of an EBV-negative B cell line. However, there is no known technique to establish EBV-negative NK cell lines.